Combined SK and K2P channel block cardioverts atrial fibrillation in 82% of cases, doubling the efficacy of single channel block

Abstract Background Inhibiting the atrial-selective SK and K2P channels represents a promising strategy for cardioverting atrial fibrillation (AF), but its efficacy has not been evaluated in a large human cohort. Objectives This study employed in-silico trials in 1000 virtual patients (i.e., clinical trials conducted in a population of virtual human subjects through modelling and simulation) to estimate the efficacy and safety of three pharmacological interventions: single and combined SK and K2P channel block. Methods A large cohort of 1000 virtual patients was developed based on human data, to cover the electrophysiological, anatomical and structural variability encountered in clinical practice. The subset of virtual patients with AF maintenance underwent pharmacological cardioversion (Figure). Results Sustained AF was observed in 654 (65%) virtual patients. In this cohort, cardioversion efficacies of 33% (213 of 654), 43% (278 of 654) and 82% (534 of 654) were obtained for single SK, single K2P and combined channel block, respectively (Figure). The cardioversion efficacy was proportional to an increase in tissue refractoriness (increase of 45.2±43.0, 71.0±55.3 and 133.0±48.4 ms in the atrial refractory period) and depended on the ionic current profile. Virtual patients cardioverted by SK channel block presented lower K2P densities (0.008±0.002 vs. 0.006±0.002 S/mF; non-cardioverted vs. cardioverted virtual patients, respectively). Similarly, a lower SK density favoured the success of K2P channel inhibition (1.87±0.24 vs. 1.46±0.5 S/mF; non-cardioverted vs. cardioverted virtual patients, respectively). Both ionic currents had a crucial role on atrial repolarization, and thus, a synergism resulted from the polypharmacological strategy (i.e., higher efficacy than the additive effects of single channel block). All three interventions, including the multi-channel block, preserved the atrial electrophysiological function (i.e., conduction velocity and calcium transient dynamics) and thus, the atrial contractile properties (safety). Conclusion In-silico trials identify the polypharmacological SK+K2P channel block as an effective and safe strategy for AF management.